U.S. patent number 6,479,692 [Application Number 09/847,229] was granted by the patent office on 2002-11-12 for methods of synthesizing acylanilides including bicalutamide and derivatives thereof.
This patent grant is currently assigned to Nobex Corporation. Invention is credited to Nnochiri N. Ekwuribe, Kenneth D. James, Jr..
United States Patent |
6,479,692 |
Ekwuribe , et al. |
November 12, 2002 |
**Please see images for:
( Certificate of Correction ) ** |
Methods of synthesizing acylanilides including bicalutamide and
derivatives thereof
Abstract
Methods of synthesizing an acylanilide ##STR1##
Inventors: |
Ekwuribe; Nnochiri N. (Cary,
NC), James, Jr.; Kenneth D. (Mebane, NC) |
Assignee: |
Nobex Corporation (Durham,
NC)
|
Family
ID: |
25300124 |
Appl.
No.: |
09/847,229 |
Filed: |
May 2, 2001 |
Current U.S.
Class: |
558/413 |
Current CPC
Class: |
C07C
253/30 (20130101); C07C 315/04 (20130101); A61P
35/00 (20180101); C07C 315/04 (20130101); C07C
317/46 (20130101); C07C 253/30 (20130101); C07C
255/60 (20130101) |
Current International
Class: |
C07C
315/00 (20060101); C07C 253/30 (20060101); C07C
253/00 (20060101); C07C 315/04 (20060101); C07C
317/00 (20060101); C07C 317/46 (20060101); C07C
255/60 (20060101); C07C 255/00 (20060101); C07C
255/50 () |
Field of
Search: |
;558/413 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
WO94/08986 |
|
Apr 1994 |
|
WO |
|
WO95/19770 |
|
Jul 1995 |
|
WO |
|
WO98/55153 |
|
Dec 1998 |
|
WO |
|
Other References
Wright et al. Journal of Medicinal Chemistry, 1978, vol. 21, No. 9,
pp 930-934.* .
Marx et al. J. Med. Chem. 1988, 31, 858-863.* .
Tucker et al., "Resolution of the Nonsteroidal Antiandrogen
4'-Cyano-3-[(4-fluorophenyl)
sulfonyl]-2-hydroxy-2-methyl-3'-(trifluoromethyl)-propionanilide
and the Determination of the Absolute Configuration of the Active
Enantiomer", J. Med. Chem., 31(4) 885-887 (1988). .
International Search Report corresponding to International
Application No. PCT/US00/41609; mailed Apr. 12, 2001. .
Tucker et al., "Nonsteroidal Antiandrogens. Synthesis and
Structure-Activity Relationships of 3-Substituted Derivatives of
2-Hydroxypropionanilides," J. Med. Chem., 31(5) 954-959 (1988).
.
Casodex (bicalutamide, 50 mg tablets) Professional Information
Brochure, <http://www.astrazeneca-us.com/pi/pib_casodex.htm>,
pp. 1-9, Jun. 26, 2000. .
Fournier et al., "(Hydroxy-2 Alkyl)-et(Hydroxy-3
Alkyl)-Phenylsulfones a Activite Hypolipidemiante," Eur. J. Med.
Chem., 17(1) 53-58 (1982) (French with English Abstract)..
|
Primary Examiner: McKane; Joseph K.
Assistant Examiner: Saeed; Kamal
Attorney, Agent or Firm: Myers Bigel Sibley & Sajovec,
P.A.
Claims
What is claimed is:
1. A method of synthesizing an acylanilide comprising: contacting a
compound having the structure of Formula I: ##STR15##
wherein R.sup.1 is substituted or unsubstituted alkyl or haloalkyl;
with a compound having the structure of Formula II: ##STR16##
wherein R.sup.2 is cyano, carbamoyl, nitro, fluoro, chloro, bromo,
iodo, or hydrogen; or alkyl, alkoxy, alkanoyl, alkylthio,
alkylsulfinyl, or alkylsulfonyl each being substituted or
unsubstituted and having up to 4 carbon atoms; or phenyl,
phenylthio, phenylsulfinyl or phenylsulfonyl each being
susbstituted or unsubstituted; R.sup.3 is cyano, carbamoyl, nitro,
fluoro, chloro, bromo or iodo; or alkyl, alkoxy, alkanoyl,
alkylthio, alkylsulfinyl, or alkylsulfonyl each being substituted
or unsubstituted and having up to 4 carbon atoms; or phenyl,
phenylthio, phenylsulfinyl or phenylsulfonyl each being substituted
or unsubstituted; and R.sup.4 is hydrogen or halogen; in the
presence of an aprotic solvent to provide a compound having the
structure of Formula III: ##STR17##
and; contacting a compound having the structure of Formula IV:
wherein R.sup.5 is substituted or unsubstituted alkyl having up to
6 carbon atoms; R.sup.6 is a direct link, or substituted or
unsubstituted alkyl having up to 6 carbon atoms; R.sup.7 is alkyl,
alkenyl, hydroxyalkyl or cycloalkyl each being substituted or
unsubstituted and having up to 6 carbons; or R.sup.7 is phenyl
which bears one, two or three substituents independently selected
from hydrogen, halogen, nitro, carboxy, carbamoyl and cyano, and
alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl,
perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio,
perfluoroalkylsulfinyl, perfluoroalkylsulfonyl, alkoxycarbonyl and
N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl,
phenylthio, phenylsulfinyl and phenylsulfonyl; or R.sup.7 is
naphthyl; or R.sup.7 is a 5- or 6-membered saturated or unsaturated
heterocyclic which contains one, two or three heteroatoms selected
from oxygen, nitrogen and sulfur, which heterocyclic may be a
single ring or may be fused to a benzo-ring, and which heterocyclic
is unsubstituted or bears one or two halogen, cyano or amino, or
alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each of up
to 4 carbon atoms, or oxy or hydroxy substituents, or which if
sufficiently saturated may bear one or two oxo substituents; and
X.sup.1 is oxygen, sulfur, sulfinyl (--SO--), sulfonyl (--SO.sub.2
--), imino (--NH--) or alkylimino (--NR.sup.8 --) where R.sup.8 is
alkyl having up to 6 carbon atoms;
with an organometallic compound to provide an intermediate
compound; and contacting the intermediate compound with the
compound of Formula III to provide an acylanilide having the
structure of Formula V: ##STR18##
2. The method according to claim 1, wherein the contacting of the
compound of Formula II with the compound of Formula I comprises
contacting the compound of Formula I with the compound of Formula
II in the presence of a carboxylic acid halogenating compound.
3. The method according to claim 2, wherein the carboxylic acid
halogenating compound is thionyl bromide or thionyl chloride.
4. The method according to claim 2, wherein the ratio on a molar
basis of carboxylic acid halogenating compound to the compound of
Formula I is between about 1:2 and about 2:1.
5. The method according to claim 1, wherein the compound of Formula
I reacts with the carboxylic acid halogenating compound to provide
an acyl halide.
6. The method according to claim 5, wherein the acyl halide reacts
with the compound of Formula II to provide the compound of Formula
III.
7. The method according to claim 6, wherein the ratio on a molar
basis of the compound of Formula II to acyl halide is between 1:4
and 1:12.
8. The method according to claim 6, wherein the ratio on a molar
basis of the compound of Formula I to acyl halide is between 1:6
and 1:10.
9. The method according to claim 1, wherein the aprotic solvent is
selected from the group consisting of N,N-dimethylacetamide,
N,N-dimethylformamide, and mixtures thereof.
10. The method according to claim 1, wherein the contacting of the
compound of Formula I with the compound of Formula II comprises
contacting the compound of Formula I with the compound of Formula
II at a temperature between about -5.degree. C. and about
40.degree. C.
11. The method according to claim 1, wherein the contacting of the
compound of Formula I with the compound of Formula II comprises
contacting the compound of Formula I with the compound of Formula
II at a temperature between about 20.degree. C. and about
30.degree. C.
12. The method according to claim 1, wherein R.sup.1 is substituted
or unsubstituted alkyl having up to 4 carbon atoms.
13. The method according to claim 1, wherein R.sup.1 is substituted
or unsubstituted alkyl having 1 or 2 carbon atoms.
14. The method according to claim 1, wherein R.sup.1 is methyl.
15. The method according to claim 1, wherein R.sup.2 is cyano,
nitro, or chloro, or perfluoroalkyl, perfluoroalkoxy,
perfluoroalkylthio, perfluoroalkylsulfinyl or
perfluoroalkylsulfonyl each having up to 4 carbon atoms; R.sup.3 is
perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio,
perfluoroalkylsulfinyl or perfluoroalkylsulfonyl each having up to
4 carbon atoms; R.sup.4 is hydrogen; and R.sup.5 is unsubstituted
alkyl.
16. The method according to claim 1, wherein R.sup.1 is methyl;
R.sup.2 is cyano; R.sup.3 is trifluoromethyl; and R.sup.4 is
hydrogen.
17. The method according to claim 1, wherein the yield of the
compound of Formula III is greater than about 70 percent.
18. The method according to claim 1, wherein the organometallic
compound is butyllithium.
19. The method according to claim 1, wherein the contacting of the
intermediate compound with the compound of Formula III comprises
slowly adding the compound of Formula III to a solution containing
the intermediate compound.
20. The method according to claim 1, wherein the ratio on a molar
basis of the compound of Formula III to intermediate compound is
between about 1:2 and about 1:10.
21. The method according to claim 1, wherein the ratio on a molar
basis of the compound of Formula III to intermediate compound is
between about 1:2 and about 1:5.
22. The method according to claim 1, wherein R.sup.5 is alkylene,
R.sup.6 is a direct link, R.sup.7 is halophenyl, and X.sup.1 is
thio, sulfinyl, or sulfonyl.
23. The method according to claim 1, wherein R.sup.5 is methylene,
R.sup.6 is a direct link, R.sup.7 is 4fluorophenyl, and X.sup.1 is
thio, sulfinyl, or sulfonyl.
24. The method according to claim 1, wherein the contacting of the
compound of Formula IV with the organometallic compound occurs at a
temperature between about -5.degree. C. and about 40.degree. C.
25. The method according to claim 1, wherein the contacting of the
compound of Formula IV with the organometallic compound occurs at a
temperature between about 20.degree. C. and about 30.degree. C.
26. The method according to claim 1, wherein an overall yield of
the compound of Formula V is greater than about 50 percent.
27. The method according to claim 1, wherein an overall yield of
the compound of Formula V is greater than about 60 percent.
28. The method according to claim 1, wherein an overall yield of
the compound of Formula V is greater than about 70 percent.
29. A method of synthesizing bicalutamide comprising: contacting a
compound having the structure of Formula VI: ##STR19##
with a compound having the structure of Formula VII; ##STR20##
in the presence of an aprotic solvent to provide a compound having
the structure of Formula VIII: ##STR21##
and; contacting a compound having the structure of Formula IX;
##STR22##
with an organometallic compound to provide an intermediate
compound; and contacting the intermediate compound with the
compound of Formula VIII to provide bicalutamide.
30. The method according to claim 29, wherein the contacting of the
compound of Formula VI with a compound of Formula VII comprises
contacting the compound of Formula VI with the compound of Formula
VII in the presence of a carboxylic acid halogenating compound.
31. The method according to claim 29, wherein the carboxylic acid
halogenating compound is thionyl bromide or thionyl chloride.
32. The method according to claim 29, wherein the ratio on a molar
basis of carboxylic acid halogenating compound to the compound of
Formula VI is between about 1:2 and about 2:1.
33. The method according to claim 29, wherein the compound of
Formula VI reacts with the carboxylic halogenating compound to
provide an acyl halide.
34. The method according to claim 29, wherein the acyl halide
reacts with the compound of Formula VII to provide the compound of
Formula VIII.
35. The method according to claim 29, wherein the ratio on a molar
basis of the compound of Formula VII to acyl halide is between
about 1:4 and about 1:12.
36. The method according to claim 29, wherein the ratio on a molar
basis of the compound of Formula VII to acyl halide is between
about 1:6 and about 1:10.
37. The method according to claim 29, wherein the aprotic solvent
is selected from the group consisting of N,N-dimethylacetamide,
N,N-dimethylformamide, and mixtures thereof.
38. The method according to claim 29, wherein the contacting of the
compound of Formula VI with a compound of Formula VII comprises
contacting the compound of Formula VI with the compound of Formula
VII at a temperature between about -5.degree. C. and about
40.degree. C.
39. The method according to claim 29, wherein the contacting of the
compound of Formula VI with a compound of Formula VII comprises
contacting the compound of Formula VI with the compound of Formula
VII at a temperature between about 20.degree. C. and about
30.degree. C.
40. The method according to claim 29, wherein the yield of the
compound of Formula VIII is greater than about 75 percent.
41. The method according to claim 29, wherein the organometallic
compound is butyllithium.
42. The method according to claim 29, wherein the contacting of the
compound of Formula IX with the organometallic compound occurs at a
temperature between about -5.degree. C. and about 40.degree. C.
43. The method according to claim 29, wherein the contacting of the
compound of Formula IX with the organometallic compound occurs at a
temperature between about 20.degree. C. and about 30.degree. C.
44. The method according to claim 29, wherein an overall yield of
bicalutamide is greater than about 50 percent.
45. The method according to claim 30, wherein an overall yield of
bicalutamide is greater than about 60 percent.
46. The method according to claim 31, wherein an overall yield of
bicalutamide is greater than about 70 percent.
Description
FIELD OF THE INVENTION
The present invention relates to methods of synthesizing organic
compounds, and more particularly to methods of synthesizing
pharmaceutical compounds and their derivatives.
BACKGROUND OF THE INVENTION
Androgen deprivation is a common treatment for persons with
prostate cancer. Various non-steroidal antiandrogens are known for
use in the treatment of prostate cancer. For example, bicalutamide
is often used in the treatment of prostate cancer. Bicalutamide is
commercially available as Casodex.RTM. (bicalutamide) from
AstraZeneca Pharmaceuticals.
The chemical name of bicalutamide is
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydro
xy-2-methyl-propanamide (+-). The structural formula of
bicalutamide is: ##STR2##
The .beta.-carbon atom in the propanamide is a chiral carbon. As a
result, bicalutamide is an optically active compound.
Such optically active compounds exist as a pair of stereoisomers
that are identical with the notable exception that they are
non-superimposable mirror images of one another. A specific
stereoisomer, such as the R isomer, may be referred to as an
enantiomer. A mixture of R and S enantiomers may be referred to as
a racemic mixture.
U.S. Pat. No. 4,636,505 to Tucker proposes various methods of
synthesizing racemic mixtures of bicalutamide and/or its
derivatives.
In Tucker et al., Nonsteroidal Antiandrogens. Synthesis and
Structure-Activity Relationships of 3-Substituted Derivatives of
2-Hydroxypropionanilides, 31 J. MED. CHEM. 954-959 (1988), the
authors propose two general synthetic routes, Scheme I and Scheme
II, that may be used to prepare acylanilides.
U.S. Pat. No. 5,985,868 to Gray proposes synthesizing racemic
mixtures of bicalutamide using methods as described in U.S. Pat.
No. 4,636,505 to Tucker, and obtaining the (-) isomer of
bicalutamide by resolution of the enantiomers of bicalutamide or of
intermediates thereto using fractional crystallization or
chromatography of diastereomeric esters of chiral acids. Gray notes
that other standard methods of resolution such as simple
crystallization and chromatographic resolution can also be
used.
In Howard Tucker et al., Resolution of the Nonsteroidal
Antiandrogen
4'-Cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-(trifluorometh
yl)-propioanilide and the Determination of the Absolute
Configuration of the Active Enantiomer, 31 J. MED. CHEM. 885-887
(1988), the authors propose an asymmetric synthesis
of(S)-bicalutamide using the N-methacrylamide of (S)-proline as a
starting material. The authors state that this approach is not
suitable for the general synthesis of the active enantiomers of
analogous anti-androgens, which would require the inaccessible and
expensive (R)-proline as a starting material.
U.S. Pat. No. 6,019,957 to Miller et al. proposes an asymmetric
synthesis of (R)-bicalutamide using (R)-proline as a starting
material.
It would be desirable to provide more effective methods for
synthesizing bicalutamide and/or its derivatives and/or
intermediates.
SUMMARY OF THE INVENTION
Embodiments of the present invention provide improved methods for
synthesizing acylanilides, particularly bicalutamide and/or its
functional derivatives. Methods according to embodiments of the
present invention may provide a racemic mixture of bicalutamide
using commercially available reagents in fewer steps than the
conventional methods described above, which may reduce the overall
synthesis time by more than 50 percent compared to these methods.
Methods according to embodiments of the present invention may
result in yields greater than 50 percent, 60 percent, 70 percent or
more. Moreover, methods according to embodiments of the present
invention may be performed at or near room temperature. These
reaction conditions may provide an energy savings when compared to
the conventional methods described above, which involve, for
example, refluxing conditions and cooling to 5.degree. C.
According to embodiments of the present invention, methods of
synthesizing an acylanilide such as bicalutamide or its functional
derivatives are provided. The methods include contacting a compound
having the structure of Formula I: ##STR3##
wherein R.sup.1 is substituted or unsubstituted alkyl or haloalkyl;
with a compound having the structure of Formula II: ##STR4##
wherein R.sup.2 is cyano, carbamoyl, nitro, fluoro, chloro, bromo,
iodo, or hydrogen; or alkyl, alkoxy, alkanoyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, perfluoroalkyl, perfluoroalkylthio,
perfluoroalkylsulfinyl, or perfluoroalkylsulfonyl each being
substituted or unsubstituted and having up to 4 carbon atoms; or
phenyl, phenylthio, phenylsulfinyl or phenylsulfonyl each being
susbstituted or unsubstituted; R.sup.3 is cyano, carbamoyl, nitro,
fluoro, chloro, bromo or iodo; or alkyl, alkoxy, alkanoyl,
alkylthio, alkylsulfinyl, alkylsulfonyl, perfluoroalkyl,
perfluoroalkylthio, perfluoroalkylsulfinyl or
perfluoroalkylsulfonyl each being substituted or unsubstituted and
having up to 4 carbon atoms; or phenyl, phenylthio, phenylsulfinyl
or phenylsulfonyl each being substituted or unsubstituted; and
R.sup.4 is hydrogen or halogen;
under conditions sufficient to provide a compound having the
structure of Formula III: ##STR5##
and treating the compound of Formula III under conditions
sufficient to provide an acylanilide. The compound of Formula I is
most preferably pyruvic acid.
In embodiments of the present invention, the compound of Formula
III is addition reacted with a compound having the structure of
Formula IV:
wherein R.sup.5 is substituted or unsubstituted alkyl having up to
6 carbon atoms; R.sup.6 is a direct link, or substituted or
unsubstituted alkyl having up to 6 carbon atoms; R.sup.7 is alkyl,
alkenyl, hydroxyalkyl or cycloalkyl each being substituted or
unsubstituted and having up to 6 carbons; or R.sup.7 is phenyl
which bears one, two or three substituents independently selected
from hydrogen, halogen, nitro, carboxy, carbamoyl and cyano, and
alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl,
perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio,
perfluoroalkylsulfinyl, perfluoroalkylsulfonyl, alkoxycarbonyl and
N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl,
phenylthio, phenylsulfinyl and phenylsulfonyl; or R.sup.7 is
naphthyl; or R.sup.7 is a 5- or 6-membered saturated or unsaturated
heterocyclic which contains one, two or three heteroatoms selected
from oxygen, nitrogen and sulfur, which heterocyclic may be a
single ring or may be fused to a benzo-ring, and which heterocyclic
is unsubstituted or bears one or two halogen, cyano or amino, or
alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each of up
to 4 carbon atoms, or oxy or hydroxy substituents, or which if
sufficiently saturated may bear one or two oxo substituents; and
X.sup.1 is oxygen, sulfur, sulfinyl (--SO--), sulfonyl (--SO.sub.2
--), imino (--NH--) or alkylimino (--NR.sup.8 --) where R.sup.8 is
alkyl having up to 6 carbon atoms;
under conditions sufficient to provide an acylanilide having the
structure of Formula V: ##STR6##
The acylanilide is most preferably bicalutamide or a functional
derivative thereof. While methods according to embodiments of the
present invention generally yield acylanilide compositions having
both R and S enantiomers in substantially equal quantities,
embodiments of the present invention resolve these acylanilide
compositions (e.g., bicalutamide products) to provide compositions
comprising more than about 60 percent R enantiomer.
Methods according to embodiments of the present invention provide a
more efficient synthesis route for acylanilides, particularly
bicalutamide and/or its functional derivatives. Methods of the
present invention may reduce the number of steps as well as the
overall synthesis time compared to conventional methods of
synthesizing bicalutamide. Moreover, methods of the present
invention may provide an overall yield that is greater than 50
percent and preferably even greater than 70 percent, which is
higher than the overall yield provided by conventional methods of
synthesizing bicalutamide. Furthermore, as methods of the present
invention may be performed at or near room temperature, these
methods may provide an energy savings when compared to conventional
methods of synthesizing bicalutamide.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention will now be described with respect to preferred
embodiments described herein. It should be appreciated however that
these embodiments are for the purpose of illustrating the
invention, and are not to be construed as limiting the scope of the
invention as defined by the claims.
As used herein, the term "functional derivative" is used to
describe a derivative of a parent compound that has the same or
substantially similar pharmacological activity as the parent
compound.
As used herein, the term "between" should be interpreted to include
the end-points. The term "up to" should be interpreted to include
the upper limit.
Methods of synthesizing an acylanilide according to embodiments of
the present invention include contacting a compound having the
structure of Formula I: ##STR7##
with a compound having the structure of Formula II: ##STR8##
under conditions sufficient to provide a compound having the
structure of Formula III: ##STR9##
and treating the compound of Formula III under conditions
sufficient to provide an acylanilide, wherein the substituents
R.sup.1 -R.sup.4 are as described below.
R.sup.1 is substituted or unsubstituted alkyl or haloalkyl. R.sup.1
is preferably substituted or unsubstituted alkyl having up to 4
carbon atoms. R.sup.1 is preferably substituted or unsubstituted
alkyl having 1 or 2 carbon atoms. R.sup.1 is more preferably
unsubstituted alkyl having 1 or 2 carbon atoms, and is most
preferably methyl.
R.sup.2 is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or
hydrogen; or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl,
alkylsulfonyl, perfluoroalkyl, perfluoroalkylthio,
perfluoroalkylsulfinyl, or perfluoroalkylsulfonyl each being
substituted or unsubstituted and having up to 4 carbon atoms (e.g.,
methylthio, ethylthio, methylsulfinyl, methylsulfonyl,
trifluoromethyl, pentafluoromethyl, trifluoromethylthio,
trifluoromethylsulfinyl or trifluoromethylsulfonyl); or phenyl,
phenylthio, phenylsulfinyl or phenylsulfonyl each being
susbstituted or unsubstituted. R.sup.2 is preferably selected from
the group consisting of cyano, nitro, chloro, perfluoroalkyl,
perfluoroalkoxy, perfluoroalkylthio, perfluoroalkylsulfinyl and
perfluoroalkylsulfonyl. R.sup.2 is most preferably cyano.
R.sup.3 is cyano, carbamoyl, nitro, fluoro, chloro, bromo or iodo;
or alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl,
perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulfinyl or
perfluoroalkylsulfonyl each being substituted or unsubstituted and
having up to 4 carbon atoms (e.g., methylthio, ethylthio,
methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoromethyl,
trifluoromethylthio, trifluoromethylsulfinyl or
trifluoromethylsulfonyl); or phenyl, phenylthio, phenylsulfinyl or
phenylsulfonyl each being substituted or unsubstituted. R.sup.3 is
preferably selected from the group consisting of perfluoroalkyl,
perfluoroalkoxy, perfluoroalkylthio, perfluoroalkylsulfinyl and
perfluoroalkylsulfonyl each having up to 4 carbon atoms. R.sup.3 is
more preferably perfluoroalkyl having 1 or 2 carbon atoms. R.sup.3
is most preferably trifluoromethyl.
R.sup.4 is hydrogen or halogen. When R.sup.4 is halogen, R.sup.4 is
preferably fluoro, chloro, bromo or iodo. R.sup.4 is preferably
hydrogen.
In a preferred embodiment, the compound of Formula I is contacted
with the compound of Formula II in the presence of a carboxylic
acid halogenating compound. The carboxylic acid halogenating
compound may be various compounds as will be understood by those
skilled in the art including, but not limited to, thionyl halides
(e.g., thionyl chloride and thionyl bromide), phosphorus trihalides
(e.g., phosphorus tribromide and phosphorus triiodide), phosphorus
pentahalides, oxalyl halides, or phosgene. The carboxylic acid
halogenating compound is preferably thionyl chloride or thionyl
bromide. The ratio on a molar basis of the carboxylic acid
halogenating compound to the compound of Formula I is preferably
between about 1:3 and about 3:1, more preferably between about 1:2
and about 2:1, and most preferably about 1:1. The compound of
Formula I is preferably activated by (reacts with) the carboxylic
acid halogenating compound to provide an acyl halide. While the
acyl halide is preferably formed in situ (i.e., in the presence of
the compound of Formula II), it is to be understood that the
compound of Formula I may be activated by the carboxylic acid
halogenating compound to provide the acyl halide in a first step,
followed by the step of contacting the acyl halide with the
compound of Formula II.
In a preferred embodiment, the acyl halide reacts with the compound
of Formula II to provide the compound of Formula III. The ratio on
a molar basis of the compound of Formula II to acyl halide is
preferably between about 1:4 and about 1:12. More preferably, the
ratio is between about 1:6 and about 1:10. Most preferably, the
ratio is between about 1:7 and about 1:9. Applicants have
unexpectedly found that using these preferred ratios of the
compound of Formula II to acyl halide may result in yields of the
compound of Formula III that are greater than about 70 percent.
The step of contacting the compound of Formula I with the compound
of Formula II may be carried out at various temperatures, as will
be understood by those skilled in the art. This step is preferably
carried out at a temperature between about -5.degree. C. and about
40.degree. C., is more preferably carried out at a temperature
between about 20.degree. C. and about 30.degree. C., and is most
preferably carried out at about room temperature. Performing this
step within the preferred ranges may result in a yield of the
compound of Formula III that is greater than 70 percent.
Additionally, these preferred temperatures may result in synthesis
methods that require less energy than conventional methods,
resulting in reduced costs.
The step of contacting the compound of Formula I with the compound
of Formula II may be carried out in the presence of various
solvents, as will be understood by those skilled in the art.
Preferably, the solvent is an aprotic solvent such as, for example,
N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl
sulfoxide, hexaniethylphosphoric triamide, tetrahydrofuran (THF),
dioxane, diethyl ether, methyl t-butyl ether (MTBE), toluene,
benzene, hexane, pentane, N-methylpyrollidinone,
tetrahydronaphthalene, decahydronaphthalene, dimethoxyethane,
methylene chloride, chloroform, 1,2-dichlorobenzene,
1,3-dimethyl-2-imidazolidinone, or a mixture thereof. More
preferably, the solvent is DMA or DMF, and most preferably the
solvent is DMA.
According to embodiments of the present invention, yields of the
compound of Formula III are preferably greater than about 70
percent, more preferably greater than about 75 percent, and most
preferably greater than about 80 percent.
The compound of Formula III may be treated under various conditions
to provide an acylanilide according to the present invention. In a
preferred embodiment, the compound of Formula III is contacted with
a compound having the structure of Formula IV:
under conditions sufficient to provide an acylanilide. Preferably,
the compound of Formula III is addition reacted with the compound
of Formula IV under conditions sufficient to provide the
acylanilide. The acylanilide preferably has a hydroxyl moiety at
its .beta. position (i.e., at a carbon atom adjacent to the
carbonyl group). More preferably, the acylanilide has the structure
of Formula V: ##STR10##
wherein the substituents R.sup.1 -R.sup.4 are as described above,
and wherein the substituents R.sup.5 -R.sup.7 and X.sup.1 are
described as follows.
R.sup.5 is substituted or unsubstituted alkyl (alkylene) having up
to 6 carbon atoms. R.sup.5 preferably is an unsubstituted alkyl
(alkylene) having 1, 2 or 3 carbon atoms. R.sup.5 is more
preferably an unsubstituted alkyl (alkylene) having 1 or 2 carbon
atoms. Most preferably, R.sup.5 is methyl (methylene).
R.sup.6 is a direct link, or substituted or unsubstituted alkylene
having up to 6 carbon atoms. Preferably, R.sup.6 is a direct link
or an unsubstituted alkylene having 1, 2 or 3 carbon atoms. More
preferably, R.sup.6 is a direct link or an unsubstituted alkylene
having 1 or 2 carbon atoms. Most preferably, R.sup.6 is a direct
link.
R.sup.7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each being
substituted or unsubstituted and having up to 6 carbons (e.g.,
methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl,
2-methylprop-2-enyl, 2-hydroxyethyl, cyclopentyl or cyclohexyl); or
R.sup.7 is phenyl which bears one, two or three substituents
independently selected from hydrogen, halogen, nitro, carboxy,
carbamoyl and cyano, and alkyl, alkoxy, alkanoyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, perfluoroalkyl, perfluoroalkoxy,
perfluoroalkylthio, perfluoroalkylsulfinyl, perfluoroalkylsulfonyl,
alkoxycarbonyl and N-alkylcarbamoyl each of up to 4 carbon atoms
and phenyl, phenylthio, phenylsulfinyl and phenylsulfonyl; or
R.sup.7 is naphthyl; or R.sup.7 is a 5- or 6-membered saturated or
unsaturated heterocyclic which contains one, two or three
heteroatoms selected from oxygen, nitrogen and sulfur, which
heterocyclic may be a single ring or may be fused to a benzo-ring,
and which heterocyclic is unsubstituted or bears one or two
halogen, cyano or amino, or alkyl, alkoxy, alkylthio, alkylsulfinyl
or alkylsulfonyl each of up to 4 carbon atoms, or oxy or hydroxy
substituents, or which if sufficiently saturated may bear one or
two oxo substituents (e.g., furyl, thienyl, pyrrolyl, pyridyl,
imidazolyl, thiazolyl, pyrimidinyl, thiadiazolyl, triazolyl,
benzimidazolyl, benzothiazolyl, indolyl, benzothienyl, benzofuryl,
quinolyl, isoquinolyl or 1,2-dihydro-2-oxoquinolyl). R.sup.7 is
preferably phenyl which bears one, two or three substituents
independently selected from hydrogen and halogen. More preferably,
R.sup.7 is halophenyl. Most preferably, R.sup.7 is
4-fluorophenyl.
X.sup.1 is oxygen, sulfur, sulfinyl (--SO--), sulfonyl (--SO.sub.2
--), imino (--NH--) or alkylimino (--NR.sup.8 --) where R.sup.8 is
alkyl having up to 6 carbon atoms. X.sup.1 is preferably sulfur,
sulfinyl (--SO--), sulfonyl (--SO.sub.2 --), imino (--NH--).
X.sup.1 is more preferably sulfur, sulfinyl (--SO--), or sulfonyl
(--SO.sub.2 --).
In a preferred embodiment, the compound of Formula IV is addition
reacted with the compound of Formula III to provide the acylanilide
of Formula V by contacting the compound of Formula IV with an
organometallic compound to provide an intermediate compound, and
contacting the intermediate compound with the compound of Formula
III to provide the acylanilide of Formula V. The organometallic
compound, which is capable of deprotonating the compound of Formula
IV, may be various organometallic compounds as will be understood
by those skilled in the art including, but not limited to, Grignard
reagents, alkyllithium, lithium diisopropylamide, lithium
hexamethyl disilazide, or a mixture thereof. The organometallic
compound is preferably alkyllithium and is more preferably
butyllithium. The intermediate compound is preferably contacted
with the compound of Formula III by slowly adding the compound of
Formula III (e.g., dropwise) to a solution containing the
intermediate compound. The ratio on a molar basis of the compound
of Formula III to intermediate compound is preferably between about
1:2 and about 1:10, and is more preferably between about 1:2 and
about 1:5. Controlling the rate at which the compound of Formula
III is added to within the preferred ranges and/or ensuring that
the ratio of the compound of Formula III to intermediate compound
is within the preferred ranges may result in yields of the
acylanilide that are higher than those obtained using conventional
synthesis methods.
The step of contacting the compound of Formula III with the
compound of Formula IV may be carried out at various temperatures,
as will be understood by those skilled in the art. However, this
step is preferably carried out at a temperature between about
-5.degree. C. and about 40.degree. C., is more preferably carried
out at a temperature between about 20.degree. C. and about
30.degree. C., and is most preferably carried out at about room
temperature. Applicants have unexpectedly found that this reaction
may be carried out at these preferred temperatures while still
obtaining a yield of acylanilide that is greater than about 85
percent. These preferred temperatures may require less energy than
conventional methods, resulting in reduced costs.
The step of contacting the compound of Formula III with the
compound of Formula IV may be carried out in the presence of
various solvents, as will be understood by those skilled in the
art. Preferably, the solvent is an aprotic solvent such as, for
example, tetrahydrofuran (THF), dioxane, ether, dimethoxyethane,
dichloromethane, benzene or a mixture thereof. More preferably, the
solvent is THF, dioxane or ether, and most preferably the solvent
is THF.
According to embodiments of the present invention, yields of the
acylanilide derived from the compound of Formula III are preferably
greater than 80 percent, more preferably greater than about 85
percent, and most preferably greater than about 90 percent.
According to embodiments of the present invention, the overall
yield of the acylanilide is preferably greater than 50 percent, is
more preferably greater than 60 percent and is most preferably
greater than 70 percent. As used herein, the overall yield is the
yield that is calculated by multiplying the yield of each
individual step in the synthetic procedure.
Preferred acylanilides that may be synthesized according to
embodiments of methods of the present invention have the structure
of Formula V above wherein R.sup.1 is methyl or trifluoromethyl,
R.sup.2 is cyano, nitro, trifluoromethyl, chloro, methyl or
methoxy, R.sup.3 is cyano, nitro, trifluoromethyl or chloro,
R.sup.4 is hydrogen, R.sup.5 is methylene, ethylene or ethylidene,
R.sup.6 is a direct link or methylene, R.sup.7 is alkyl, alkenyl,
hydroxyalkyl or cycloalkyl each having up to 6 carbon atoms, or
phenyl which is unsubstituted or which bears one fluoro, chloro,
cyano, nitro, methoxy or methylthio substituent, or thienyl,
imidazolyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyridyl or
pyrimidinyl which is unsubstituted or which bears one chloro, bromo
or methyl substituent, and X.sup.1 is oxygen, sulfur, sulfinyl,
sulfonyl, imino or methylimino.
Particularly preferred acylanilides that may be synthesized
according to embodiments of methods of the present invention have
the structure of Formula V above wherein R.sup.1 is methyl, R.sup.2
is cyano or nitro, R.sup.3 is trifluoromethyl, R.sup.4 is hydrogen,
R.sup.5 is methylene, R.sup.6 a direct link, R.sup.7 is alkyl
having up to 3 carbon atoms, preferably ethyl, or is allyl, phenyl,
p-fluorphenyl, thiazol-2-yl, 4-methylthiazol-2-yl,
5-methyl-1,3,4-thiadiazol-2-yl or 2-pyridyl, and X.sup.1 is sulfur,
sulfonyl or sulfinyl.
The following acylanilides are preferably synthesized according to
embodiments of methods of the present invention:
3-chloro-4-cyano-N-((2-hydroxy-2-methyl-3-ethylthio)propionyl)aniline;
3-chloro-4-cyano-N-((2-hydroxy-2-methyl-3-ethylsulfonyl)propionyl)aniline;
3-trifluoromethyl-4-cyano-N-((2-hydroxy-2-methyl-3-phenylsulfonyl)propiony
l)aniline;
3-trifluoromethyl-4-cyano-N-((2-hydroxy-2-methyl-3-ethylsulfonyl)propionyl
)aniline;
3-trifluoromethyl-4-cyano-N-((2-hydroxy-2-methyl-3-phenylsulfonyl)propiony
l)aniline;
3-trifluoromethyl-4-nitro-N-((2-hydroxy-2-methyl-3-ethylsulfonyl)propionyl
)aniline;
3-chloro-4-nitro-N-((2-hydroxy-2-methyl-3-phenylthio)propionyl)aniline;
3-trifluoromethyl-4-nitro-N-((2-hydroxy-2-methyl-3-(thiazol-2yl)thio)propi
onyl)aniline; 3-tri
fluoromethyl-4-nitro-N-((2-hydroxy-2-methyl-3-allylthio)propionyl)aniline;
3-trifluoromethyl-4-nitro-N-((2-hydroxy-2-methyl-3-(p-fluorophenyl)thio)pr
opionyl)aniline; 3-trifluoromethyl-4-nitro-N-((2-hydroxy
-2-methyl-3-(pyrid-2ylthio)propionyl)aniline;
3-trifluoromethyl-4-nitro-N-((2-hydroxy-2-methyl-3-(5-methyl-1,3,4-thiadia
zol-2-ylthio)propiony
3-trifluoromethyl-4-nitro-N-((2-hydroxy-2-methyl-3-(4-methylthiazol-2-ylth
io)propionyl)aniline;
3-trifluoromethyl-4-nitro-N-((2-hydroxy-2-methyl-3-(pyrid-2-ynsulfonyl)pro
pionyl)aniline;
3-trifluoromethyl-4-nitro-N-((2-hydroxy-2-methyl-3-(p-fluorophenylsulfonyl
)propionyl)aniline;
3-trifluoromethyl-4-cyano-N-((2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propi
onyl)aniline;
3-trifluoromethyl-4-cyano-N-((2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propion
yl)aniline;
3-trifluoromethyl-4-cyano-N-((2-hydroxy-2-methyl-3-methylthiopropionyl)ani
line;
3-trifluoromethyl-4-cyano-N-((2-hydroxy-2-methyl-3-(p-fluorophenylthio)pro
pionyl)aniline;
3-trifluoromethyl-4-cyano-N-((2-hydroxy-2-methyl-3-(p-fluorophenylsulfonyl
)propionyl)aniline.
In a particularly preferred embodiment, bicalutamide is synthesized
according to methods of the present invention. The reaction
conditions (e.g., temperature, compound ratios, solvents, etc.) are
as described above and will not be further described. According to
this particularly preferred embodiment, a compound having the
structure of Formula VI: ##STR11##
is contacted with a compound having the structure of Formula VII:
##STR12##
under conditions sufficient to provide a compound having the
structure of Formula VIII: ##STR13##
The compound of Formula VIII is treated under conditions sufficient
to provide bicalutamide. Preferably, the compound of Formula VIII
is contacted with a compound having the structure of Formula IX:
##STR14##
under conditions sufficient to provide bicalutamide. Typically, the
compound of Formula VIII is addition reacted with a compound having
the structure of Formula IX.
As discussed in U.S. Pat. No. 5,985,868, to Gray, the (-)isomer of
bicalutamide may be obtained by resolution of the enantiomers of
racemic bicalutamide. Examples of standard methods of resolution
known to those skilled in the art include simple crystallization
and chromatographic resolution. (See, for example, G. Subramanian,
A Practical Approach to Chiral Separations by Liquid
Chromatography, John Wiley & Sons, 1994; Thomas E. Beesley,
Raymond P. W. Scott, Chiral Chromatography, John Wiley & Son
Ltd., 1999; Satinder Ahuja, Chiral Separations: Applications and
Technology, American Chemical Society, 1996); E. L. Eliel,
Stereochemistry of Carbon Compounds, McGraw Hill (1962); and Wilen
and Lochmuller, "Tables of Resolving Agents," J. chromatography
113, 283-302 (1975)). In a preferred method, a racemic mixture is
separated using high pressure liquid chromatography (HPLC) (see
Krstulovic, A. M., ed. Chiral Separations by HPLC: Applications to
Pharmacological Compounds, Halsted Press, 1989).
Optically active compounds have the ability to rotate the plane of
polarized light. In describing an optically active compound, the
prefixes D and L or R and S are used to denote the absolute
configuration of the molecule about its chiral center(s). The
prefixes "d" and "l" or (+) and (-) are used to denote the optical
rotation of the compound (i.e., the direction in which a plane of
polarized light is rotated by the optically active compound). The
"l" or (-) prefix indicates that the compound is levorotatory
(i.e., rotates the plane of polarized light to the left or
counterclockwise) while the "d" or (+) prefix means that the
compound is dextrarotatory (i.e., rotates the plane of polarized
light to the right or clockwise). The sign of optical rotation, (-)
and (+), is not related to the absolute configuration of the
molecule, R and S.
Thus, in a further aspect of the invention, the R and S components
of the racemic mixture prepared according to the synthetic method
of the invention are separated to provide compositions having a
majority of R or a majority of S enantiomer. In a preferred aspect
of the invention, the R and S components of the racemic mixture
prepared according to the synthetic method of the invention are
separated to provide compositions comprising greater than 75
percent R or S, more preferably greater than 90 percent R or S, and
still more preferably greater than 99 percent R or S. In a highly
preferred embodiment, the separated compositions have substantially
all R enantiomer or substantially all S enantiomer. The R form is
preferred as the more active of the two enantiomers.
Acylanilides synthesized by the methods disclosed herein can be
prepared in the form of their pharmaceutically acceptable salts.
Pharmaceutically acceptable salts are salts that retain the desired
biological activity of the parent compound and do not impart
undesired toxicological effects. Examples of such salts are (a)
acid addition salts formed with inorganic acids, for example
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, nitric acid and the like; and salts formed with organic acids
such as, for example, acetic acid, oxalic acid, lactic acid,
tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic
acid, methanesulfonic acid, p-toluenesulfonic acid,
naphthalenedisulfonic acid, polygalacturonic acid, and the like;
(b) salts formed from elemental anions such as chlorine, bromine,
and iodine, and (c) salts derived from bases, such as ammonium
salts, alkali metal salts such as those of sodium and potassium,
alkaline earth metal salts such as those of calcium and magnesium,
and salts with organic bases such as dicyclohexylamine and
N-methyl-D-glucamine.
Acylanilides synthesized by the methods described above may be
formulated for administration in a pharmaceutical carrier in
accordance with known techniques. See, e.g., Remington, The Science
And Practice of Pharmacy (9.sup.th Ed. 1995). In the manufacture of
a pharmaceutical formulation according to the invention, the
acylanilide (and/or the physiologically acceptable salts thereof)
is typically admixed with, inter alia, an acceptable carrier. The
carrier must, of course, be acceptable in the sense of being
compatible with any other ingredients in the formulation and must
not be deleterious to the patient. The carrier may be a solid or a
liquid, or both, and is preferably formulated with the compound as
a unit-dose formulation, for example, a tablet, which may contain
from 0.01 or 0.5 percent to 95 percent or 99 percent by weight of
the acylanilide. One or more acylanilides synthesized by the
methods described above may be incorporated in the formulations of
the invention, which may be prepared by any of the well known
techniques of pharmacy consisting essentially of admixing the
components, optionally including one or more accessory
ingredients.
The formulations of the invention include those suitable for oral,
rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral
(e.g., subcutaneous, intramuscular, intradermal, or intravenous),
topical (i.e., both skin and mucosal surfaces, including airway
surfaces) and transdermal administration, although the most
suitable route in any given case will depend on the nature and
severity of the condition being treated and on the nature of the
particular acylanilide which is being used.
Formulations suitable for oral administration may be presented in
discrete units, such as capsules, cachets, lozenges, or tables,
each containing a predetermined amount of the acylanilide; as a
powder or granules; as a solution or a suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
Such formulations may be prepared by any suitable method of
pharmacy which includes the step of bringing into association the
acylanilide and a suitable carrier (which may contain one or more
accessory ingredients as noted above). In general, the formulations
of the invention are prepared by uniformly and intimately admixing
the acylanilide with a liquid or finely divided solid carrier, or
both, and then, if necessary, shaping the resulting mixture. For
example, a tablet may be prepared by compressing or molding a
powder or granules containing the acylanilide, optionally with one
or more accessory ingredients. Compressed tablets may be prepared
by compressing, in a suitable machine, the compound in a
free-flowing form, such as a powder or granules optionally mixed
with a binder, lubricant, inert diluent, and/or surface
active/dispersing agent(s). Molded tablets may be made by molding,
in a suitable machine, the powdered compound moistened with an
inert liquid binder.
Formulations suitable for buccal (sub-lingual) administration
include lozenges comprising the acylanilide in a flavoured base,
usually sucrose and acacia or tragacanth; and pastilles comprising
the compound in an inert base such as gelatin and glycerin or
sucrose and acacia.
Formulations of the present invention suitable for parenteral
administration comprise sterile aqueous and non-aqueous injection
solutions of the acylanilide, which preparations are preferably
isotonic with the blood of the intended recipient. These
preparations may contain anti-oxidants, buffers, bacteriostats and
solutes which render the formulation isotonic with the blood of the
intended recipient. Aqueous and non-aqueous sterile suspensions may
include suspending agents and thickening agents. The formulations
may be presented in unitdose or multi-dose containers, for example
sealed ampoules and vials, and may be stored in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid carrier, for example, saline or water-for-injection
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described. For example, in one
aspect of the present invention, there is provided an injectable,
stable, sterile composition comprising a compound of Formula (I),
or a salt thereof, in a unit dosage form in a sealed container. The
compound or salt is provided in the form of a lyophilizate which is
capable of being reconstituted with a suitable pharmaceutically
acceptable carrier to form a liquid composition suitable for
injection thereof into a subject. The unit dosage form typically
comprises from about 10 mg to about 10 grams of the compound or
salt. When the compound or salt is substantially water insoluble, a
sufficient amount of emulsifying agent which is physiologically
acceptable may be employed in sufficient quantity to emulsify the
compound or salt in an aqueous carrier. One such useful emulsifying
agent is phosphatidyl choline.
Formulations suitable for rectal administration are preferably
presented as unit dose suppositories. These may be prepared by
admixing the acylanilide with one or more conventional solid
carriers, for example, cocoa butter, and then shaping the resulting
mixture.
Formulations suitable for topical application to the skin
preferably take the form of an ointment, cream, lotion, paste, gel,
spray, aerosol, or oil. Carriers which may be used include
petroleum jelly, lanoline, polyethylene glycols, alcohols,
transdermal enhancers, and combinations of two or more thereof.
Formulations suitable for transdermal administration may be
presented as discrete patches adapted to remain in intimate contact
with the epidermis of the recipient for a prolonged period of time.
Formulations suitable for transdermal administration may also be
delivered by iontophoresis (see, for example, Pharmaceutical
Research 3 (6):318 (1986)) and typically take the form of an
optionally buffered aqueous solution of the acylanilide. Suitable
formulations comprise citrate or bistris buffer (pH6) or
ethanolwater and contain from 0.1 to 0.2M active ingredient.
All starting materials used in the procedures described herein are
either commercially available or can be prepared by methods known
in the art using commercially available starting materials.
The present invention will now be described with reference to the
following examples. It should be appreciated that these examples
are for the purposes of illustrating aspects of the present
invention, and do not limit the scope of the invention as defined
by the claims.
EXAMPLE 1
Synthesis of
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-oxo-propionamide
Pyruvic acid (3.0 mL; 43 mmol) and thionyl chloride (3.1 mL; 43
mmol) were added simultaneously via syringes to a stirring solution
of 4-cyano-3-trifluoromethyl-aniline (1.00 g; 5.38 mmol) in 20 mL
of dry DMA at room temperature. After 10 minutes, the reaction
mixture was diluted with ether and extracted 3 times with saturated
NaHCO.sub.3 and 4 times with cold saturated brine. The organic
layer was dried with MgSO.sub.4 and concentrated by rotary
evaporation. The product was purified by silica gel chromatography
(ethyl acetate/hexanes [1/1]). Yield 1.11 g (81%); mp
147-148.degree. C.; MS (FAB.sup.+) 257 (M+1); .sup.1 H NMR .delta.
9.12 (s, 1H), 8.15 (s, 1H), 8.01 (d, J=8.5), 7.84 (d, J=8.5, 1H),
2.59 (s, 3H); .sup.13 C NMR .delta. 195.66, 157.71, 140.29, 135.90,
134.2, 122.01, 121.85, 117.44, 115.12, 105.55, 23.92; .sup.19 F NMR
.delta. -62.76. IR: 3330, 3112, 3065, 1719, 1540. UV:
.lambda..sub.max 214, 248, 288. Anal. Calculated for C.sub.11
H.sub.7 F.sub.3 N.sub.2 O.sub.2 : C, 51.57; H, 2.75; N, 10.94.
Found: C, 51.69; H, 2.81; N, 10.86.
EXAMPLE 2
Synthesis of
N-(4-Cyano-3-trifluoromethyl-phenyl)-3-(4-fluoro-benzenesulfonyl)-2-hydrox
y-2-methyl-propionamide
Butyllithium (13.0 mmol) was added to a stirring solution of
4-fluorophenyl methyl sulfone (2.49 g; 14.3 mmol) in 13 mL of dry
THF at room temperature. After 1 hr, a solution of the keto-amide
(1.11 g; 4.34 mmol) prepared above in Example 1 in 4 mL of dry THF
was added slowly to the stirring reaction. After 20 minutes, the
reaction was brought to a neutral pH with 1M HCl. The contents were
diluted with ethyl acetate and extracted with 1M HCl and saturated
brine. The organic layer was dried with MgSO.sub.4 and concentrated
by rotary evaporation. After purification by silica gel
chromatography (CH.sub.2 Cl.sub.2 /ethyl acetate [4/1]), the
product was crystallized from ethyl acetate--petroleum ether. Yield
1.67 g (90%); mp 187.degree. C. ; MS (FAB.sup.+) 431 (M+I), 453
(M+Na); 1H NMR .delta. 9.08 (s, 1H), 7.98 (a, 1H), 7.87-7.92 (m,
2H), 7.79-7.78 (m, 2H), 7.15-7.20 (m, 2H), 5.04 (s, 1H), 3.97 (d,
J=14.5, 1H), 3.49 (d, J=14.5, 1H), 1.62 (s, 3H); .sup.19 F NMR
.delta.-62.74, -101.49. IR: 3432, 3338, 3106, 2921, 1699, 1586,
1525. UV: .lambda..sub.max 216, 270. Anal. Calculated for C.sub.18
H.sub.14 F.sub.4 N.sub.2 O.sub.4 S: C, 50.23; H, 3.28; N, 6.51.
Found: C, 50.35; H, 3.16; N, 6.35.
In the specification, there has been disclosed typical preferred
embodiments of the invention and, although specific terms are
employed, they are used in a generic and descriptive sense only and
not for purposes of limitation, the scope of the invention being
set forth in the following claims.
* * * * *
References